ABSTRACT As the 76 million baby boomers age, dental caries continues to pose a significant challenge for older Americans (Dye et al., 2007, 2015). While the effectiveness of fluoride in preventing dental caries in children has been long recognized (Marinho et al., 2003; NIH Consensus Conference, 2001), it is only recently that its effectiveness in caries prevention in adults has been established (Griffin et al., 2007; Gibson et al., 2011). Meta-analysis (Griffin et al., 2007) indicates that 25% of new caries in adults can be prevented using self- and professionally applied or community water fluoridation. However, their systematic review also noted the relative paucity of high-quality studies in adults, thus highlighting the need for our proposed project. More recently, in 2013, the American Dental Association (ADA) issued clinical recommendations for topical fluoride use for caries prevention (Weyant et al., 2013). However, for adults 18 years and older, the topical fluoride recommendations are based on expert opinion, extrapolating the evidence from permanent teeth of children, since no such studies exist in adults. In order to fill this important gap in knowledge, ADA identified the need for research regarding fluoride effectiveness in adults, and particularly the study of subpopulations of adults such as those at highest risk of developing caries and those older than 65 and adults at extremely high risk of developing caries. ADA also highlighted the need for comparative effectiveness studies of different fluoride strategies in these populations. We have already begun to fill some of the knowledge gaps regarding fluoride effectiveness in adults. Using comprehensive electronic patient records, we completed a retrospective analysis of longitudinal data, and found that clinical fluoride treatments effectively prevented new restorative care in patients at high risk for dental caries, both in patient-level analyses (Jurasic et al., 2014) and VA patient population-level analyses (Gibson et al., 2014). However, it remains unclear whether varying types, combinations and/or intensity of fluoride are more effective, and to what extent patients? systemic health influence fluoride effectiveness. Moreover, as dental caries is a multi-factorial disease process, such studies also need to collect data on key factors such as medical comorbidities, medication use, access to preventive dental services, and race/ethnicity. Our proposed use of existing data thus represents a highly efficient approach to conducting robust analyses on the effectiveness of fluoride in adult caries prevention. Thus, our proposed study aims to: Aim 1. Determine which (if any) types, combinations and intensities of fluoride are more effective at preventing new caries-related restorations and extractions in adult patients at high risk for caries. Aim 2. Determine to what extent patients? medication use is associated with fluoride effectiveness in preventing new caries-related restorations and extractions in adult patients at high risk for caries.